Title: Artesunate-heparin conjugate based nanocapsules with improved

pharmacokinetics to combat malaria

Authors: Muhammad Ismail, Yawei Du, Longbing Ling, Xinsong Li*

Journal: International Journal of Pharmaceutics

Accepted,2019

Abstract

10 Artesunate-heparin conjugate (ART-HEP) based nanocapsules as drug delivery vehicle was

developed for intracellular release of ART in malaria therapy. Owing both hydrophobic and

hydrophilic moieties, the conjugate was successfully self-assembled into artesunate-heparin

nanocapsules (ART-HEP-NCPs) with lower critical micelle concentration (CMC) of about 20

μg/mL. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed

15 that ART-HEP-NCPs has an average hydrodynamic diameter of 112.1 nm with a negatively

charged surface (-11.2 mV) and typical micellar nanostructure, respectively. Interestingly, such

modification achieved high drug loading efficiency (DLE) of ART (29.3 wt.%), which is

significantly higher than already reported conventional ART-loaded nanoparticles. The

nanocapsules demonstrated lower in vitro ART release under neutral physiological environment

20 (33.81%) but higher release rate was observed in simulated acidic microenvironment (92.74%) in

70 h test. This behavior of ART-HEP-NCPs will facilitate the intracellular release of ART under

slightly acidic parasitic food vacuole for effective antimalarial effect. Storage stability and

hemolytic studies exhibited that ART-HEP based nanocapsules were stable and safe for

intravenous (i.v) injection. Notably, ART-HEP-NCPs has promising internalization into

25 Plasmodium infected red blood cells (iRBCs) and also displayed in vitro inhibitory effect against

P. falciparum 3D7 with half-maximal inhibitory concentration (IC50) of 10.16 nM, which was

slightly higher than free ART (IC50 6.27 nM). This expected slightly lower inhibitory effect of

polymeric prodrug could be ascribed to the gradual release of ART from the polymer chain over

time. More importantly, the in vivo pharmacokinetics study indicated that the nanoscale

30 characteristic of nanocapsules substantially contributed to the extended circulation of ART in

blood. In conclusion, such multifunctional ART-HEP-NCPs with higher ART loading and

extended half-life could be a promising platform for targeted antimalarial drug delivery.